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Bone minerals may be more complex than the prevailing opinion suggests. Understanding its biomaterial properties in health and disease may address fundamental geo/biomorphological ambiguities recurrent within its calcified cancellous hierarchy of macro-, micro-, and nano-skeletal networks. (i) There is evidence that the outer mineral macroskeleton of interconnected trabeculae (150 µm diameter) is modulated according to axes of tensile stress by permeating arrays of periosteal Sharpey’s fibres (collagen type III/VI, 5–25 µm thick) studded with tenascin organiser protein. (ii) Its substructural mineral microskeleton is a reticulation of bridged and deformable calcium phosphate/carbonate microspheres (about 1 µm diameter). These organically enshrouded (e.g., bone sialoprotein, osteocalcin, osteopontin) objects, configured by the adhesive organiser protein fibronectin and tempered by trace elements (e.g., Si, Mg, Fe, Al), display differential histochemistry (e.g., acid phosphatase, carbonic anhydrase) and anomalous traits (tetracycline binding, gram-positive microbial staining and nucleic acid staining affinity). The calcified microspheres are intracellular fabrications of osteocyte cohorts developed within “switched on” Golgi cisternae prior to aggregation at the extracellular calcification front in chains and looped assemblies. (iii) Within each microsphere, a less dense centre is encircled by a mineral nanoskeleton of beaded filaments (5 nm in diameter) transmutable in electron density, with a trait for lateral fusion into ladder-like struts, stays and senescent fenestrated plates, constituting domains of microparticle slip and crystal fracture. The evidence suggests a bone mineral biosystem of integrated complexity within which a particulate assemblage at the animate: inanimate calcification front resembles a colonial construct of prokaryote-like, Golgi-fabricated objects calcified with phosphate and harbouring a resident biochemistry. A self-contained “Petrified Microbiome” is proposed to be orchestrated according to a biodynamic primordial paradigm.

Abstract Arctic sea ice has shifted from a perennial (older, thicker ice) to a seasonal (younger, thinner) ice regime, leading to the increasingly common belief that shipping through Canada’s Northwest Passage is becoming more viable. Here, we use the Risk Index Outcome values derived from the Polar Operational Limit Assessment Risk Indexing System and analyze recent changes to shipping season lengths along individual sections of the Northwest Passage routes from 2007 to 2021. Results show that multi-year ice flushed southward from high-latitude regions maintains the so-called choke points along certain route sections, reducing overall shipping season length. There is considerable spatiotemporal variability in shipping season lengths along the southern and northern routes. Specifically, parts of the northern route exhibit a decrease of up to 14 weeks over the 15 years. The variability of shipping season and, in particular, the shortening of the season will impact not only international shipping but also resupply and the cost of food in many Arctic communities, which require a prompt policy response.

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Abstract Free-ranging cats (Felis catus) are globally distributed invasive carnivores that markedly impact biodiversity. Here, to evaluate the potential threat of cats, we develop a comprehensive global assessment of species consumed by cats. We identify 2,084 species eaten by cats, of which 347 (16.65%) are of conservation concern. Islands contain threefold more species of conservation concern eaten by cats than continents do. Birds, reptiles, and mammals constitute ~90% of species consumed, with insects and amphibians being less frequent. Approximately 9% of known birds, 6% of known mammals, and 4% of known reptile species are identified in cat diets. 97% of species consumed are

With the exponential growth of mobility data generated by IoT, social networks, and mobile devices, there is a pressing need to address privacy concerns. Our work proposes methods to reduce the computation of privacy risk evaluation on mobility datasets, focusing on reducing background knowledge configurations and matching functions, and enhancing code performance. Leveraging the unique characteristics of trajectory data, we aim to minimize the size of combination sets and directly evaluate risk for trajectories with distinct values. Additionally, we optimize efficiency by storing essential information in memory to eliminate unnecessary computations. These approaches offer a more efficient and effective means of identifying and addressing privacy risks associated with diverse mobility datasets.

Abstract Analysis of circulating tumor DNA (ctDNA) to monitor cancer dynamics and detect minimal residual disease has been an area of increasing interest. Multiple methods have been proposed but few studies have compared the performance of different approaches. Here, we compare detection of ctDNA in serial plasma samples from patients with breast cancer using different tumor‐informed and tumor‐naïve assays designed to detect structural variants (SVs), single nucleotide variants (SNVs), and/or somatic copy‐number aberrations, by multiplex PCR, hybrid capture, and different depths of whole‐genome sequencing. Our results demonstrate that the ctDNA dynamics and allele fractions (AFs) were highly concordant when analyzing the same patient samples using different assays. Tumor‐informed assays showed the highest sensitivity for detection of ctDNA at low concentrations. Hybrid capture sequencing targeting between 1,347 and 7,491 tumor‐identified mutations at high depth was the most sensitive assay, detecting ctDNA down to an AF of 0.00024% (2.4 parts per million, ppm). Multiplex PCR targeting 21–47 tumor‐identified SVs per patient detected ctDNA down to 0.00047% AF (4.7 ppm) and has potential as a clinical assay.

The study objective was to evaluate the interaction between corticotrophin releasing factor (CRF) receptor signaling and prophylactic antibiotic administration on intestinal physiology in newly weaned and transported pigs. Pigs (n = 56; 5.70 ± 1.05 kg) were weaned (20.49 ± 0.64 d), a blood sample was taken, and then pigs were given an intraperitoneal injection of saline (SAL; n = 28 pigs) or a CRF receptor antagonist (CRFA; n = 28 pigs; 30 μg/kg body weight; Astressin B), and then were transported in a livestock trailer for 12 h and 49 min. A second and third intraperitoneal injection was given at 4 h 42 min and 11 h 36 min into the transport process, respectively. Following transport, 4 SAL and 4 CRFA pigs were blood sampled and euthanized. The remaining 48 pigs were individually housed and given dietary antibiotics [AB; n = 12 SAL and 12 CRFA pigs; chlortetracycline (441 ppm) + tiamulin (38.6 ppm)] or no dietary antibiotics (NAB; n = 12 SAL and 12 CRFA pigs) for 14 d post-transport. Blood was collected at 12 h and on d 3, 7, and 14, and then pigs were euthanized on d 7 (n = 24) and d 14 (n = 24) post-weaning and transport. Circulating cortisol was reduced (p = 0.05) in CRFA pigs when compared to SAL pigs post-weaning and transport. On d 7, jejunal villus height and crypt depth was greater overall (p < 0.05) in AB-fed pigs versus NAB-fed pigs. On d 14, ileal crypt depth was reduced (p = 0.02) in CRFA pigs when compared to SAL pigs. Jejunal CRF mRNA abundance tended to be reduced (p = 0.09) on d 7 in CRFA pigs versus SAL pigs. On d 14, jejunal tumor necrosis factor-alpha was reduced (p = 0.01) in AB-fed pigs versus NAB-fed pigs. On d 7, change in glucose short-circuit current tended to be increased (p = 0.07) in CRFA pigs fed the AB diet when compared to CRFA pigs fed the NAB diet. In conclusion, CRFA pigs and pigs fed AB had some similar biological intestinal function measures post-weaning and transport.

Background New approaches are needed to improve and destigmatize remediation in undergraduate medical education (UME). The COVID-19 pandemic magnified the need to support struggling learners to ensure competency and readiness for graduate medical education (GME). Clinical skills (CS) coaching is an underutilized approach that may mitigate the stigma of remedial learning. Methods A six-month CS coaching pilot was conducted at Harvard Medical School (HMS) as a destigmatized remedial learning environment for clerkship and post-clerkship students identified as ‘at risk’ based on objective structured clinical examinations (OSCE). The pilot entailed individual and group coaching with five faculty, direct bedside observation of CS, and standardized patient encounters with video review. Strengths-based coaching principles and appreciative inquiry were emphasized. Results Twenty-three students participated in the pilot: 14 clerkship students (cohort 1) and 9 post-clerkship students (cohort 2). All clerkship students (cohort 1) demonstrated sustained improvement in CS across three OSCEs compared to baseline: at pilot close, at 6-months post pilot, and at 21-24 months post-pilot all currently graduating students (10/10, 100%) passed the summative OSCE, an HMS graduation requirement. All post-clerkship students (cohort 2) passed the HMS graduation OSCE (9/9,100%). Feedback survey results included clerkship students (9/14; 64%) and post-clerkship students (7/9; 78%); all respondents unanimously agreed that individual coaching was “impactful to my clinical learning and practice”. Faculty and leadership fully supported the pilot as a destigmatized and effective approach to remediation. Conclusion Remediation has an essential and growing role in medical schools. CS coaching for remedial learning can reduce stigma, foster a growth mindset, and support sustained progress for ‘at risk’ early clerkship through final year students. An “implementation template” with suggested tools and timelines can be locally adapted to guide CS coaching for UME remediation. The CS coaching pilot model is feasible and can be generalized to many UME programs.

The composition of the extracellular matrix (ECM) in nervous tissue plays an important role in controlling neuronal outgrowth and synapse development. Changes in both protein and glycosaminoglycan components of the ECM occur with tissue injury and may affect neuron growth. To investigate neuron responses to alterations in fibronectin (FN), a major component of the wound ECM, we grew cortical neurons on cell-derived decellularized matrices composed of wild type FN (FN+/+) or of a mutant form of FN (FNΔ/+) from which the III13 heparin-binding site had been deleted by CRISPR-Cas 9 gene editing. The most significant effect of the mutant FN was a reduction in dendrite outgrowth. Not only were dendrites shorter on mutant FNΔ/+-collagen (COL) matrix than on wild type (FN+/+-COL) matrix, but the number of dendrites and dendritic spines per neuron and the spine densities were also dramatically reduced on FNΔ/+-COL matrices. Mass spectrometry and immunostaining identified a reduction in tenascin-C (TN-C) levels in the mutant matrix. TN-C is an ECM protein that binds to the III13 site of FN and modulates cell-matrix interactions and has been linked to dendrite development. We propose that TN-C binding to FN in the wound matrix supports dendrite and spine development during repair of damaged neural tissue. Overall, these results show that changes in ECM composition can dramatically affect elaboration of neurites and support the idea that the ECM microenvironment controls neuron morphology and connectivity.

Summary: Background: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in β-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. Methods: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. Findings: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with β-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. Interpretations: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. Funding: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.

Modern batteries are highly complex devices. The cells contain many components—which in turn all have many variations, both in terms of chemistry and physical properties. A few examples: the active materials making the electrodes are coated on current collectors using solvents, binders and additives; the multicomponent electrolyte, contains salts, solvents, and additives; the electrolyte can also be a solid ceramic, polymer or a glass material; batteries also contain a separator, which can be made of glass fibres, polymeric, ceramic, composite, etc. Moving up in scale all these components are assembled in cells of different formats and geometries, coin cells and Swagelok cells for funamental testing and understanding, and pouch, prismatic and cylindrical cells for application. Given this complexity dictated by so many components and variations, there is no wonder that addressing the crucial issue of true sustainability is an extremely challenging task. How can we make sure that each component is sustainable? How can the performance can be delivered using more sustainable battery components? What actions do we need to take to address battery sustainability properly? How do we actually qualify and quantify the sustainability in the best way possible? And perhaps most importantly; how can we all work—academia and battery industry together—to enable the latter to manufacture more sustainable batteries for a truly cleaner future? This Roadmap assembles views from experts from academia, industry, research institutes, and other organisations on how we could and should achieve a more sustainable battery future. The palette has many colours: it discusses the very definition of a sustainable battery, the need for diversification beyond lithium-ion batteries (LIBs), the importance of sustainability assessments, the threat of scarcity of raw materials and the possible impact on future manufacturing of LIBs, the possibility of more sustainable cells by electrode and electrolyte chemistries as well as manufacturing, the important role of new battery chemistries, the crucial role of AI and automation in the discovery of the truly sustainable batteries of the future and the importance of developimg a circular battery economy.

Background: Solid retroperitoneal masses in children are frequent in pediatrics’ oncology. The diagnosis must be prompt and precise in order to initiate appropriate treatment options. These treatment options takes into account; the histological type, staging, associated comorbidities and the child's tolerance to mainly chemotherapy as well radiotherapy which is often employed. This preliminary study is part of a better understanding of retroperitoneal solid cancer in black children, more specifically in Cameroon and in particular on the data concerning the epidemiology, the diagnostic process, the therapeutic options, the results of the treatment and related difficulties to children's care in daily practice. Objectives: To determine the clinical, therapeutic and prognostic profile of children treated for solid retroperitoneal masses and also assess the health-related quality of life the cancer survivors in a tertiary hospital in Cameroon. Materials and method: We carried out a descriptive cohort study at the Mother and Child Center of the Chantal Biya Foundation (MCC-CBF), in Cameroon. The study concerned children followed in the pediatric oncology center from 2007 to 2019 who presented with a solid retroperitoneal tumor and received complete management. The health-related quality of life was assessed using the ''Pediatric Quality of life Scale'' (PedsQL). The data was analyzed with IBM_SPSS software version 20.0. The analysis of survival data was carried out according to the Kaplan Meier's method. The alpha risk was set at a threshold of 5% Results: A total of 84 children with solid retroperitoneal masses were included in our study with 74 cases of nephroblastoma and 10 cases of neuroblastoma. The median age of the children at diagnosis was 3.9 years. The main clinical manifestations found were; abdominal distension, abdominal pain, abdominal mass, weight loss, anorexia and prolonged fever. Out of the 74 cases of nephroblastoma, 73% of the cases were localized tumors while on the other hand 90% of the neuroblastomas were metastasized. The course of treatment was neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy in 80 children. Four children with tumor rupture underwent primary surgery without neoadjuvant chemotherapy. The 2-year survival rate was 71.6% for nephroblastoma and 30% for neuroblastoma, respectively. The health-related quality of life of the surviving children was rated as satisfactory. Conclusion: Solid retroperitoneal masses in child are a group of curable cancer in our context. Postoperative morbidity is lower, with almost zero mortality. The health-related quality of life of children surviving after surgery is good

Abstract The zoonotic pathogen Salmonella enterica serotype Enteritidis (SE) causes severe disease in young chickens. Restriction on antibiotic use requires alternative SE control strategies such as nutritional solutions to improve the resistance of chickens. In this study, chickens were fed long-chain glucomannan (GM) or standard diet and challenged with SE at seven days of age. During 21 days post-infection (dpi), we determined numbers and responsiveness of natural killer (NK) and T cells in ileum and spleen, and SE-specific antibody titers in serum. Microbiota compositions in ileum and caeca were determined, as well as correlations of these with numbers and function of immune cells. Some of the samples in the control group had numerically higher CFUs than the GM-treated group. In addition, the relative abundance of SE based on DNA assessment was significantly lower at 21 dpi upon GM supplementation. At 3 dpi, numbers of intraepithelial NK cells were significantly higher, while activation of intraepithelial NK cells (7 dpi), numbers of intraepithelial cytotoxic CD8+ T cells (14 dpi) and SE-specific antibodies (14 dpi) were numerically higher. Furthermore, relative abundance of the commensal lactic acid bacteria (LAB) significantly increased with GM supplementation post-infection. Higher relative abundance of streptococci was associated with reduced SE in ileal and caecal contents at 21 dpi. Relative abundance of streptococci negatively correlated with SE counts and positively correlated with NK cell activation and SE-specific antibodies, which suggests involvement of the commensal LAB in NK cell responsiveness. These results indicate that GM supplementation modulates the immune system, intestinal microbiota and impacts SE infection of young chickens.

Aphasia is a common complication of stroke, often causing significant morbidity. To the authors' knowledge, no stroke recovery practice guidelines incorporating pharmacologic or noninvasive brain stimulation (NIBS) therapies for poststroke aphasia (PSA) exist. The aim of this article is to provide a comprehensive review of the evidence regarding pharmacologic and NIBS treatment in PSA. An exhaustive single database search assessing treatment for PSA was performed from 2010 to 2020, resulting in 1876 articles. Articles evaluating either pharmacologic management or NIBS were included. Case reports, case series, original research, systematic reviews, and meta-analyses were allowed. Pharmacologic treatment studies included were represented by the following medication classes: cholinergic, dopaminergic, gamma-aminobutyric acid agonists and derivatives, N-methyl-D-aspartate receptor antagonists, serotonergic, and autonomic agents. NIBS treatment studies regarding transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) were evaluated. No strong evidence was found for any medication to improve PSA. However, the benefit of a medication trial may outweigh the risk of side effects as some evidence exists for functional recovery. Regarding NIBS, weak evidence exists for the treatment effect of tDCS and rTMS on PSA. While additional research is needed, the literature shows promise, especially in chronic phase of stroke when traditional treatment options may be exhausted. More evidence with larger studies and standardized study design is needed.

BackgroundDigital mental health interventions (DMHIs) have been increasingly deployed to bridge gaps in mental health care, particularly given their promising efficacy. Nevertheless, attrition among DMHI users remains high. In response, human support has been studied as a means of improving retention to and outcomes of DMHIs. Although a growing number of studies and meta-analyses have investigated the effects of human support for DMHIs on mental health outcomes, systematic empirical evidence of its effectiveness across mental health domains remains scant. ObjectiveWe aimed to summarize the results of meta-analyses of human support versus no support for DMHI use across various outcome domains, participant samples, and support providers. MethodsWe conducted a systematic meta-review of meta-analyses, comparing the effects of human support with those of no support for DMHI use, with the goal of qualitatively summarizing data across various outcome domains, participant samples, and support providers. We used MEDLINE, PubMed, and PsycINFO electronic databases. Articles were included if the study had a quantitative meta-analysis study design; the intervention targeted mental health symptoms and was delivered via a technology platform (excluding person-delivered interventions mediated through telehealth, text messages, or social media); the outcome variables included mental health symptoms such as anxiety, depression, stress, posttraumatic stress disorder symptoms, or a number of these symptoms together; and the study included quantitative comparisons of outcomes in which human support versus those when no or minimal human support was provided. ResultsThe results of 31 meta-analyses (505 unique primary studies) were analyzed. The meta-analyses reported 45 effect sizes; almost half (n=22, 48%) of them showed that human-supported DMHIs were significantly more effective than unsupported DMHIs. A total of 9% (4/45) of effect sizes showed that unsupported DMHIs were significantly more effective. No clear patterns of results emerged regarding the efficacy of human support for the outcomes assessed (including anxiety, depression, posttraumatic stress disorder, stress, and multiple outcomes). Human-supported DMHIs may be more effective than unsupported DMHIs for individuals with elevated mental health symptoms. There were no clear results regarding the type of training for those providing support. ConclusionsOur findings highlight the potential of human support in improving the effects of DMHIs. Specifically, evidence emerged for stronger effects of human support for individuals with greater symptom severity. There was considerable heterogeneity across meta-analyses in the level of detail regarding the nature of the interventions, population served, and support delivered, making it difficult to draw strong conclusions regarding the circumstances under which human support is most effective. Future research should emphasize reporting detailed descriptions of sample and intervention characteristics and describe the mechanism through which they believe the coach will be most useful for the DMHI.

Abstract Background: The number of older adults living with companion animals (pets) is increasing worldwide. While evidence revealing positive relationships between companion animals and healthy aging is well established, there is a dearth of research regarding companion animal death and subsequent human grieving. Some emerging research suggests that grief over companion animal death is often discounted or even unrecognized (disenfranchised) by others. The extent and consequences of disenfranchised grief (DG) are poorly understood. This study deepens our understanding of older adults’ experiences of DG in relation to companion animal death. Methods: Participants from Alberta, Canada, were recruited through social media platforms to participate in an online questionnaire that collected demographic information and standardized measures of companion animal attachment, bereavement, and DG. Results: The majority of the 98 participants were between 60 and 70 years of age, female, and living alone. Following their companion animal’s death, 38.1% identified a decrease in physical activity, and 47% reported that their emotional health had declined. One-third identified that they needed to be careful about who they disclosed their grief, as they were not certain that they would be supported. This group had a significantly greater likelihood of perceived decrease in physical health, and they were more likely to score higher on the Pet Bereavement Questionnaire. Conclusions: This study adds weight to the emergent body of evidence highlighting companion animal bereavement as a legitimate and impactful health and well-being issue. The study found that DG is experienced by a sizable group of older adults following their companion animal’s death and that many participants perceived that socially legitimized recognition of loss and accompanying bereavement resources were lacking. These shortfalls contribute to health risks that negatively affect older adults’ ability to successfully age in the community.

Background: The large South African population of people with disabilities presents unique challenges for training organisations because there is no training model that accommodates the demands of all disabilities. The site of the research was a private, nonprofit training institution with disability-friendly infrastructure which did not adequately prepare students for employment. Objectives: The intention was to interrogate training models used at the institution, from the perspectives of students, facilitators and prospective employers. As there was no suitable assessment instrument, one that was fit for purpose was developed. The Adaptable Component-based Assessment Model (ACA Model) was the result. Method: A case study using mixed methods was employed. The interpretive research paradigm allowed for purposive sampling. This article reports on the qualitative first phase of the study. The ACA Model was developed, and iterative applications provided information about areas that needed improvement before the second phase was initiated. Results: The results all indicated that the existing programmes needed to be evaluated with the view for improvement. Various training models can be used to train students with disabilities, but they need to be assessed to ensure that they are integrated, holistic and student centred. Because different accommodations need to be taken into account for various disabilities, the ideal assessment model needs to be adaptable. Conclusion: The ACA Model is an appropriate assessment model as it is based on individual learner affordances, workplace affordances, the holistic development of students and workplace absorption. Contribution: The research contributes to knowledge and practice as the resultant ACA Model can be used to the benefit of students and education institutions. The model can be tailored to the needs of all groups of students, especially those with disabilities.

Abstract Non-contact infrared thermometers (NCITs) are being widely used during the COVID-19 pandemic as a temperature-measurement tool for screening and isolating patients in healthcare settings, travelers at ports of entry, and the general public. To understand the accuracy of NCITs, a clinical study was conducted with 1113 adult subjects using six different commercially available NCIT models. A total of 60 NCITs were tested with 10 units for each model. The NCIT-measured temperature was compared with the oral temperature obtained using a reference oral thermometer. The mean difference between the reference thermometer and NCIT measurement (clinical bias) was different for each NCIT model. The clinical bias ranged from just under − 0.9 °C (under-reporting) to just over 0.2 °C (over-reporting). The individual differences ranged from − 3 to + 2 °C in extreme cases, with the majority of the differences between − 2 and + 1 °C. Depending upon the NCIT model, 48% to 88% of the individual temperature measurements were outside the labeled accuracy stated by the manufacturers. The sensitivity of the NCIT models for detecting subject’s temperature above 38 °C ranged from 0 to 0.69. Overall, our results indicate that some NCIT devices may not be consistently accurate enough to determine if subject’s temperature exceeds a specific threshold of 38 °C. Model-to-model variability and individual model accuracy in the displayed temperature were found to be outside of acceptable limits. Accuracy and credibility of the NCITs should be thoroughly evaluated before using them as an effective screening tool.

Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice.

There are many security challenges in IoT, especially related to the authentication of restricted devices in long-distance and low-throughput networks. Problems such as impersonation, privacy issues, and excessive battery usage are some of the existing problems evaluated through the threat modeling of this work. A formal assessment of security solutions for their compliance in addressing such threats is desirable. Although several works address the verification of security protocols, verifying the security of components and their non-locking has been little explored. This work proposes to analyze the design-time security of the components of a multi-factor authentication mechanism with a reputation regarding security requirements that go beyond encryption or secrecy in data transmission. As a result, it was observed through temporal logic that the mechanism is deadlock-free and meets the requirements established in this work. Although it is not a work aimed at modeling the security mechanism, this document provides the necessary details for a better understanding of the mechanism and, consequently, the process of formal verification of its security properties.

Abstract Background Companion animal death is a common source of grief, although the extent and context of that grief is poorly understood, especially in older adulthood. The aim of this multiple-methods study was to develop a greater understanding of the impact of companion animal death on older women living alone in the community, as older women are a distinct at-risk group, and the supports that should be available to help these individuals with their grief. Methods Participants were recruited from across Alberta, a Canadian province, through seniors’ organizations, pet rescue groups, and social media groups of interest to older women. After completing a pre-interview online questionnaire to gain demographic information and standardized pet attachment and grief measures data, participants were interviewed through the Zoom ® computer program or over the telephone. An interpretive description methodology framed the interviews, with Braun and Clarke’s 6-phase analytic method used for thematic analysis of interview data. Results In 2020, twelve participants completed the pre-interview questionnaires and nine went on to provide interview data for analysis. All were older adult (age 55+) women, living alone in the community, who had experienced the death of a companion animal in 2019. On the standardized measures, participants scored highly on attachment and loss, but low on guilt and anger. The interview data revealed three themes: catastrophic grief and multiple major losses over the death of their companion animal, immediate steps taken for recovery, and longer-term grief and loss recovery. Conclusions The findings highlight the importance of acknowledging and addressing companion animal grief to ensure the ongoing well-being and thus the sustained successful aging-in-place of older adult women in the community.

Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.

Abstract Background The Service Availability and Readiness Assessment surveys generate data on the readiness of health facility services. We constructed a readiness index related to malaria services and determined the association between health facility malaria readiness and malaria mortality in children under the age of 5 years in Burkina Faso. Methods Data on inpatients visits and malaria-related deaths in under 5-year-old children were extracted from the national Health Management Information System in Burkina Faso. Bayesian geostatistical models with variable selection were fitted to malaria mortality data. The most important facility readiness indicators related to general and malaria-specific services were determined. Multiple correspondence analysis (MCA) was employed to construct a composite facility readiness score based on multiple factorial axes. The analysis was carried out separately for 112 medical centres and 546 peripheral health centres. Results Malaria mortality rate in medical centres was 4.8 times higher than that of peripheral health centres (3.5% vs. 0.7%, p

Abstract Viticulture negatively impacts the environment, biodiversity, and human health; however, despite the widely acknowledged challenges that this intensive agricultural activity poses to sustainable development, measures to reduce its invasiveness are constantly being deferred or rebuffed. Constraints to change are linked to vine cultivation methods, the impacts of climate change on vine resilience and disease sensitivity, and socio-economic models, as well as growing criticisms from society. Research and training have thus far failed to provide solutions or mobilise stakeholders on a large scale. Such resistance to sustainable practices development calls into question the effectiveness of knowledge production systems and relations between scientists, winegrowers, and society: Have scientific disciplines overly isolated themselves from each other and from the wider society to the point of losing the capacity to incorporate alternative forms of knowledge and reasoning and achieve collaborative action? Herein, we describe our findings from a participatory action research project that began in Westhalten, France, in 2013 and ultimately spread to Switzerland and Germany over the next 6 years. We show that participatory action research can mobilise long-term collaborations between winegrowers, NGOs, advisers, elected officials, members of civil society, and researchers, despite differing visions of viticulture and the environment. The epistemological framework of this research promotes consensus-building by valuing complexity and dissensus in knowledge and reasoning such that all actors are involved in experimentation and the production of results. From these findings, consensus statements were collectively elaborated in qualitative and quantitative registers. Once acknowledged by the scientific community, these consensus statements became shareable knowledge. We propose that this renewed interdisciplinarity associating the human and social sciences with agronomic and biological sciences in collaboration with stakeholders produces actionable knowledge that mobilises and engages winegrowers to conceive and implement sustainable viticulture on a transnational scale.

Abstract Background NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer. Methods We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers. Results We found that the MDA-MB-175 fusion—originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1—is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1’s nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers. Conclusions Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management.

Abstract This article supplements a recent Perspective by Scorrano et al. in Nature Communications [10 [ (1)]:1287] in which the properties and functions of inter-organelle membrane contact sites were summarized. It is now clear that inter-organelle membrane contact sites are widespread in eukaryotic cells and that diverse pairs of organelles can be linked via unique protein tethers. An appropriate definition of what constitutes an inter-organelle membrane contact site was proposed in the Perspective. In addition, the various experimental approaches that are frequently used to study these organelle associations, as well as the advantages and disadvantages of each of these methods, were considered. The nature of the tethers that link the pairs of organelles at the contact sites was discussed in detail and some biological functions that have been ascribed to specific membrane contact sites were highlighted. Nevertheless, the functions of most types of organelle contact sites remain unclear. In the current article I have considered some of the points raised in the Perspective but have omitted detailed information on the roles of membrane contact sites in biological functions such as apoptosis, autophagy, calcium homeostasis and mitochondrial fusion. Instead, I have provided some background on the initial discovery of mitochondria-endoplasmic reticulum membrane contact sites, and have focussed on the known roles of membrane contact sites in inter-organelle lipid transport. In addition, potential roles for membrane contact sites in human diseases are briefly discussed.

Abstract Background Social media and academic literature suggest that more people are using cannabis to treat their own or their dog’s chronic pain. This study identifies the reasons people use cannabis products to treat their own pain or their dog’s pain and explores whether these products have fulfilled their expectations. Methods An anonymous, online survey was used to collect quantitative and qualitative self-report data on respondents’ perceptions, motivations and expectations about their or their dog’s chronic pain and cannabis use. The analyses are based on U.S. adults who reported using cannabis products to treat their own (N = 313) or their dog’s (N = 204) chronic pain. Quantitative responses from the two groups were compared using Chi-Square tests and qualitative data were analyzed using a thematic analysis. Results Human patients and dog owners reported similar motivations for using cannabis products to treat chronic pain, with the more popular reasons being that cannabis products are natural, are preferred over conventional medication, are believed to be the best treatment or good treatment option for pain. Similar proportions of human patients and dog owners reported that the use of cannabis products fulfilled their expectations (86% vs. 82% respectively, χ2 (1, 200) = .59, p = .32). The qualitative data revealed that their expectations were met by reducing pain, increasing relaxation, and improving sleep, coping, functionality and overall well being. Additionally, the qualitative data suggests that cannabis products offer a return to normalcy and a restored sense of self to human and dog patients. Conclusions The results suggest that people choose cannabis products because they are natural and a possible solution to managing chronic pain when conventional medicines have not been effective. Most people report that their expectations regarding pain management are fulfilled by these products. More accurate assessments are vital, however, for understanding both the objective biomedical and subjective socioemotional benefits of cannabis products for effective pain management for human and dog patients. In addition, objective factual information regarding cannabis products for effective pain management in humans and dogs is needed. It is recommended that both physicians and veterinarians work towards feeling more comfortable proactively broaching the subject of cannabis use with additional training and education.

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased “lipotoxicity,” improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., “C24:0/C16:0”), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e′. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD's mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.

Abstract Background We determined the association between ratios of plasma ceramide species of differing fatty‐acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community‐based sample. Methods We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia‐free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long‐chain (C24:0, C22:0) to long‐chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results During a median 6.5 year follow‐up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox‐proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross‐sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions Higher plasma ratios of very long‐chain to long‐chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community‐based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults.

Objective: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations. Methods: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment. Results: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09). Conclusion: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

From its earliest beginnings, the university was not designed for women, and certainly not for women of color. Women of color in the United States are disproportionately under-represented in academia and are conspicuous by their absence across disciplines at senior ranks, particularly at research-intensive universities. This absence has an epistemic impact and affects future generations of scholars who do not see themselves represented in the academy. What are the barriers to attracting, advancing, and retaining women faculty of color in academia? To address this question we review empirical studies that document disparities in the assessment of research, teaching, and service in academia that have distinct implications for the hiring, promotion, and professional visibility of women of color. We argue that meaningful change in the representation, equity, and prestige of women faculty of color will require validating their experiences, supporting and valuing their research, creating opportunities for their professional recognition and advancement, and implementing corrective action for unjust assessment practices.

Meaningful progress in improving employment outcomes for people with intellectual and developmental disabilities continues to be elusive, despite 40 years of investment in research, policy, and supports. This article reviews the current state of employment for individuals with intellectual and developmental disabilities (IDD) and describes policy, practice, and individual factors that influence employment outcomes. Research suggests the need for a holistic approach to change that addresses systems-level strategy, policy, and fiscal investment while strengthening individual experiences with employment and related day services. Recommendations address strengthening the implementation of employment policy, developing pathways to employment, and engaging individuals with IDD and, in particular, individuals with diverse social characteristics in reflecting on the quality of their experiences and supports.

Niemann-Pick disease type C1 (NPC1) is a fatal, neurodegenerative, cholesterol storage disorder. With new therapeutics in clinical trials, there is an urgency to improve diagnostics and monitor therapeutic efficacy with biomarkers. In this study, we sought to define the structure of an unknown lipid biomarker for NPC1 with [M + H]+ ion at m/z 509.3351, previously designated as lysoSM-509. The structure of N-palmitoyl-O-phosphocholineserine (PPCS) was proposed for the lipid biomarker based on the results from mass spectrometric analyses and chemical derivatizations. As no commercial standard is available, authentic PPCS was chemically synthesized, and the structure was confirmed by comparison of endogenous and synthetic compounds as well as their derivatives using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PPCS is the most abundant species among N-acyl-O-phosphocholineserines (APCS), a class of lipids that have not been previously detected in biological samples. Further analysis demonstrated that all APCS species with acyl groups ranging from C14 to C24 were elevated in NPC1 plasma. PPCS is also elevated in both central and peripheral tissues of the NPC1 cat model. Identification of APCS structures provide an opportunity for broader exploration of the roles of these novel lipids in NPC1 disease pathology and diagnosis.

Cholesterol is an essential structural component of cellular membranes and precursor molecule for oxysterol, bile acid, and hormone synthesis. The study of intracellular cholesterol trafficking pathways has been limited in part due to a lack of suitable cholesterol analogues. Herein, we developed three novel diazirine alkyne cholesterol probes: LKM38, KK174, and KK175. We evaluated these probes as well as a previously described diazirine alkyne cholesterol analogue, trans-sterol, for their fidelity as cholesterol mimics and for study of cholesterol trafficking. LKM38 emerged as a promising cholesterol mimic because it both sustained the growth of cholesterol-auxotrophic cells and appropriately regulated key cholesterol homeostatic pathways. When presented as an ester in lipoprotein particles, LKM38 initially localized to the lysosome and subsequently trafficked to the plasma membrane and endoplasmic reticulum. LKM38 bound to diverse, established cholesterol binding proteins. Through a detailed characterization of the cellular behavior of a panel of diazirine alkyne probes using cell biological, biochemical trafficking assays and immunofluorescence approaches, we conclude that LKM38 can serve as a powerful tool for the study of cholesterol protein interactions and trafficking.

Early life stress (ELS) precedes alterations to neuro-immune activation, which may mediate an increased risk for stress-related psychiatric disorders, potentially through alterations of central kynurenine pathway (KP) metabolites, the latter being relatively unexplored. We hypothesized that ELS in a non-human primate model would lead to a reduction of neuroprotective and increases of neurotoxic KP metabolites. Twelve adult female bonnet macaques reared under conditions of maternal variable foraging demand (VFD) were compared to 27 age- and weight-matched non-VFD-exposed female controls. Baseline behavioral observations of social affiliation were taken over a 12-week period followed by the first cerebrospinal fluid (CSF) sample. Subjects were then either exposed to a 12-week repeated separation paradigm (RSP) or assigned to a “no-RSP” condition followed by a second CSF. We used high-performance liquid chromatography for kynurenine (KYN), tryptophan, 5-hydroxyindoleacetic acid, kynurenic acid (KYNA), and anthranilic acid (ANTH) as a proxy for quinolinic acid determination. At baseline, social affiliation scores were reduced in VFD-reared versus control subjects. CSF log KYNA and log KYNA/KYN ratio were lower in VFD-reared versus control subjects. CSF log KYNA/KYN was positively correlated with CSF log ANTH in VFD only (r = 0.82). Controlling for log KYNA/KYN, log ANTH was elevated in VFD-reared subjects versus controls. CSF log KYNA/KYN obtained post-RSP was positively correlated with mean social affiliation scores during RSP, specifically in VFD. ELS is associated with a reduced neuroprotective and increased neurotoxic pathway products. That the two contrasting processes are paradoxically correlated following ELS suggests a cross-talk between two opposing KP enzymatic systems.

How does the way people first interact affect communicative effectiveness? Does it matter if you meet someone via video-chat first or via text first? In Study 1, attitudes towards three common communication media were surveyed. In general, respondents preferred face-to-face interactions and messaging platforms over phone calls. In Study 2, participants first met via either video-chat or messaging, and then switched to the other modality. Dyads who met first via text performed worse on an anagram task than those who met first via video. However, those who met first via text were more confident in their performance. How people first get to know each other impacts how they feel about their conversations and how effectively they work together.